Ovarian cancer is the most lethal of the gynecological cancers. Ovarian cancer is diagnosed annually in nearly a quarter of a million women globally, and is responsible for 140,000 deaths each year. In the U.S., 21,980 new cases and 14,270 deaths were estimated in 2014. Khabele, D., “The therapeutic potential of class I selective histone deacetylase inhibitors in ovarian cancer,” Frontiers in Oncology, Vol. 4, pp. 1-8, 1 (2014). Current treatment for ovarian cancer entails a combination of cytoreductive surgery and platinum-based chemotherapy. Id. Despite even the best initial results, most ovarian cancers relapse with recurrent tumors and options for treatment of recurrent disease are restricted by few effective drugs and frequent dose-limiting toxicities of traditional drugs. Id. New approaches are urgently needed that can extend the disease-free interval, re-sensitize tumors to platinum-based drugs, and minimize toxic effects.
Histone deacetylases (HDACs) are a family of enzymes that regulate gene expression by removing acetyl groups from lysine residues on histones and non-histone proteins. Inhibition of HDACs with small molecules has led to the development of HDAC inhibitors, primarily for use in hematologic malignancies. HDAC inhibitors are a structurally diverse set of chemical compounds traditionally classified into four major categories: hydroxamic acids (e.g., vorinostat); benzamides (e.g., MS-275); short aliphatic acids (e.g., valproic acid, VPA); and cyclic peptides (e.g., romidepsin or depsipeptide). Id. HDAC inhibitors increase acetylation of histones and other non-histone proteins, resulting in changes in gene expression, induction of apoptosis, and inhibition of angiogenesis and metastasis. They are effective for use in cancer treatment because of their ability to differentiate between normal cells and cancer cells at therapeutic dosages. HDAC inhibitors, for example, vorinostat (SAHA, ZOLINZA®) and romidepsin (FK228, ISTODAX®), are known to be effective in treating hematological malignancies. In fact, vorinostat and romidepsin are FDA-approved for the treatment of cutaneous and peripheral T-cell lymphoma. However, clinical trials with an HDAC inhibitor as a single agent in the treatment of solid tumors, including ovarian cancer, have produced poor results. Khabele, Abstract.
Nuclear factor-kappa B (NF-κB) is a transcription factor that comprises five different proteins and is found in all cell types. It is involved in cellular responses to stimuli, such as cytokines and stress, and plays a key role in regulating the immune response to infection and inflammation. http://www.tocris.com/newsletter/IKK_web-alert.html. In unstimulated cells, NF-κB dimers are sequestered in the cytoplasm in an inactive complex with inhibitory protein, called inhibitor of kappa B (IκB). IκB inactivates NF-κB by masking the nuclear localization signals (NLS), and preventing translocation of NF-κB proteins to the nucleus.
Activation of NF-κB occurs via degradation of IκB, a process that is initiated by IκB phosphorylation by IκB kinase (IKK). Phosphorylated IκB is then ubiquitinated and degraded by the proteasome. Once IκB is degraded, NF-κB translocates to the nucleus and induces transcription of NF-κB-dependent genes. In addition to phosphorylating IκB, resulting in its proteasomal degradation, IKK can also directly phosphorylate the p65 subunit of NF-κB, resulting in its transcriptional activation. Vancurova, I, et al., “Regulation and function of nuclear IκBα in inflammation and cancer,” Am. J. Clin. Exp. Immunol., Vol. 1, No. 1, pp. 56-66 (2012).
NF-κB regulates the genes involved in inflammation, cell proliferation, and cell survival, and NF-κB activity is constitutively increased in many human tumors. Constitutive activation of NF-κB can result from a mutation in NF-κB itself or in genes that control its activity, e.g., IκB. Specifically, constitutive activation of NF-κB is observed in a number of lymphoma subtypes. Deng, C., et al., “The Novel IKK2 Inhibitor LY2409881 Potently Synergizes with Histone Deacetylase Inhibitors in Preclinical Models of Lymphoma through the Downregulation of NF-κB,” Clin. Cancer Res., Vol. 21, No. 1, pp. 134-145 (2015). One of the genes that is regulated by NF-κB is the pro-inflammatory and pro-angiogenic chemokine interleukin-8 (IL-8) that induces tumor cell survival, proliferation, angiogenesis, and metastasis. IL-8 production is increased in many types of cancer, and correlates with cancer progression and poor prognosis. Blocking IKK and NF-κB activation can stop tumor cell proliferation and induce cell death. Therefore, IKK inhibitors have been identified for use in the treatment of cancers.
IKK inhibitors have been used in combination with HDAC inhibitors in the treatment of hematological malignancies, such as lymphoma and leukemia, but not for the treatment of solid tumor cancers because each has shown disappointing results as a single agent in the treatment of solid tumor cancers, such as ovarian cancer and drug-resistant tumors.